The loss of the sense of smell is a common symptom of chronic rhinosinusitis (CRS) that markedly diminishes the quality of life of affected patients. Traditionally, olfactory loss has been thought to occur by obstruction of the olfactory cleft or damage to the olfactory neuroepithelium subsequent to inflammation. While this is true in some cases, it is likely that there are other cellular and molecular mechanisms that modulate olfactory function in CRS. A hallmark feature of CRS is the presence of inflammatory cytokine mediators produced by infiltrating leukocytes. Among these cytokines, tumor necrosis factor alpha (TNF-1) is particularly interesting because of its central role in CRS- associated inflammation and its recognized functions in regulating neurogenesis and patterned neuronal cell death. The PI has recently generated a mouse model of inducible TNF-1 expression specifically within the olfactory epithelium. TNF-1 induction in this model causes loss of odorant sensitivity and, under certain conditions, death of olfactory sensory neurons (OSNs). In many cell types, TNF-1 and other cytokines relevant in CRS directly alter calcium homeostasis through multiple signaling pathways including activation of MAP kinases and the transcription factor NF-:B. It is our hypothesis that inflammatory mediators present in CRS cause olfactory dysfunction through their direct effects on OSNs and olfactory progenitor cells. Our induced olfactory inflammation mouse model provides a novel tool with which to study the effect of acute and chronic inflammation on the function and structure of the olfactory epithelium. The central hypothesis of this proposal is that inflammation induced by TNF-1 promotes the loss of olfaction through three principal mechanisms: 1) desensitization of OSNs to odorants; 2) induction of OSN apoptosis; and 3) inhibition of olfactory epithelial regeneration. An integrated approach involving physiological and molecular techniques will be utilized to dissect the underlying mechanisms of olfactory loss in chronic olfactory inflammation. The experiments described in this proposal will afford new insights into the signaling pathways that mediate inflammatory cytokine effects on neural function and potentially lead to new therapeutic approaches in treating CRS-associated olfactory loss. [unreadable] [unreadable] [unreadable]